Despite the existence of many useful antibiotics, bacterial infections remain a major problem affecting human and animal health, agriculture, and industrial processes. The continued emergence of resistant bacteria heightens the need for the identification of new and effective antibacterial agents. The most advantageous of the antibacterial agents are those which can be used to selectively control bacteria without posing any health hazards for humans or animals. The identification of such agents is fraught with difficulties and uncertainties due in part to the many biochemical similarities between all living organisms. The identification of antibacterial agents remains an empirical process requiring extensive effort and the investment of substantial resources.
Bacteria in general synthesize a variety of extracellular glycans which provide structural integrity and a protective "wall" to the cell. Inhibition of the biosynthesis of this "wall" has been a favored approach in the design of drugs for the treatment of infectious disease because animal cells do not synthesize these walls. Most of the widely used and clinically effective antibiotics, such as the penicillins (cephalosporins) and vancomycin, function because they inhibit bacterial cell wall biosynthesis. The metabolic targets of each of these drugs are enzymes involved in the polymerization of the glycan chain and the cross-linking of the glycan chains. The biochemical pathway involved in cell wall synthesis is shown in FIG. 1.
One component of importance in cell wall biosynthesis is a C.sub.55 isoprenoid lipid called undecaprenyl phosphate (C.sub.55 --P). This lipid acts as a catalyst in gathering and transferring carbohydrate residues to the growing cell wall. The synthesis of a repeating saccharide unit of peptidoglycan occurs on the C.sub.55 isoprenoid lipid at the cytoplasmic face to the inner plasma membrane. This saccharide unit, while linked to the lipid, is translocated to the paraplasmic surface of the membrane where these sugars are transferred to the growing peptidoglycan.
The translocation of the C.sub.55 isoprenoid lipid back to the cytosolic compartment may be an energy dependant process. In an alternate pathway, the C.sub.55 isoprenoid lipid is hydrolyzed to free undecaprenol (C.sub.55 OH), which is translocated in an energy independent or low energy process to the cytosolic side of the membrane. At the cytosolic membrane surface, undecaprenol is then phosphorylated by a ATP-dependant undecaprenol kinase to regenerate the lipid, undecaprenyl phosphate, necessary for the next saccharide translocation process. The undecaprenol kinase enzyme is encoded by the gene known as bac-A which has been described by Cain et al. [Cain, Brian D., Peter J. Norton, Willis Eubanks, Harry S. Nick, Charles M. Allen (1993) "Amplification of the bacA Gene Confers Bacitracin Resistance to Escherichia coli" J.Bacteriology 175(12):3784-3789].
Although de novo biosynthesis provides the bulk of the initial pool of undecaprenyl phosphate, two alternative mechanisms are involved in maintaining an adequate pool size of C55--P for cell growth: 1) regeneration of undecaprenyl phosphate from the hydrolysis of undecaprenyl phosphate following saccharide transfer to the growing glycan; and 2) phosphorylation of free undecaprenol. The phosphorylation of free undecaprenol has previously been described as a "salvage" pathway. Although the enzyme responsible for the phosphorylation of free undecaprenol was crystallized over 20 years ago, there is no information published about its mechanism of action and little is known about its metabolic function.